TH-302 is a hypoxia-activated prodrug in clinical development for the treatment of cancer. See PCT Publication Nos. 2007/002931; 2008/083101; 2010/048330; 2012/006032; 2012/009288; 2012/135757; 2012/142520; and U.S. provisional patent application Ser. No. 61/593,249 filed on 31 Jan. 2012, each of which is incorporated herein by reference. TH-302 releases the DNA cross-linking bromo-isophosphoramidate (sometimes referred to as bromo-isophosphoramide) mustard (Br-IPM) under hypoxic conditions. TH-302 induces G2/M arrest at low concentrations and a pan-cell cycle arrest at high concentrations.
When DNA damage occurs, a signal transduction pathway cascade is activated in response to the damage, which transmits signals to the downstream effectors that connect with the cell cycle machinery. Checkpoint kinase 1 (Chk1) is a vital link between the upstream sensors of the DNA damage checkpoints and the cell cycle effectors. See Cancer Biology & Therapy (2004) 3:3, 305-313, incorporated herein by reference. Generally, cell cycle progression is interrupted at the stage where the cell was when injured to give the cell time to repair the damage by activating DNA damage response and repair pathways. In recent years, Chk1 inhibitors have been studied for use in combination with DNA damaging anticancer agents that cause S and G2/M arrest in attempts to increase the efficacy of the underlying cancer treatment. However, no Chk1 inhibitor has been approved for cancer treatment alone or in combination with another anti cancer agent.